B-cell lymphoma is a significant clinical problem that is rising in incidence and prevalence as the American population ages. The most common subtype of B-cell lymphoma, diffuse large B-cell lymphoma, is a disease which arises from mature B-cells at various stages of antigenic activation and differentiation into plasma cells. Recently, it has become apparent that microRNAs (miRNAs), small RNA molecules that regulate gene expression, are intimately involved in oncogenesis and developmental regulation. This proposal outlines a 5-year research plan to unravel the role of two tumor- suppressor miRNAs, miR-34a and miR-146a, in B-cell lymphoma pathogenesis, to understand their developmental roles in B-cell activation and to evaluate their mechanism of action. We propose the following hypotheses: (i) miR-34a and miR-146a regulate B-cell activation and plasma cell differentiation (ii) Dysregulation of these two miRNAs contributes to the pathogenesis of B-cell malignancies and (iii) the mechanism of their action in both development and malignancy relates to their regulation of several critical targets. We will use a combination of genetically defined murine models, retroviral transduction systems, bone marrow transplantation, high-throughput approaches, bioinformatics, and hypothesis-driven investigation of individual targets to understand the role of miRNAs in development and oncogenesis. This proposal is eminently translational and future directions include the development of diagnostic and therapeutic applications of miRNAs. All of the necessary methodology, training, resources, mentorship and personnel are in place for the successful completion of these goals. The completion of these goals promises to significantly increase our understanding of critical biological and pathological processes. Perhaps most importantly, it will bring forward a highly promising approach to treatment of patients who suffer from devastating malignant diseases of B-cells.